DCC-3116 for Solid Tumors

Not currently recruiting at 11 trial locations

Overseen By Clinical Team

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Deciphera Pharmaceuticals LLC

Must not be taking: CYP3A4 inhibitors, P-gp inducers

Disqualifiers: CNS metastases, Heart disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called inlexisertib for individuals with advanced or metastatic solid tumors that have a specific mutation known as RAS/MAPK. Researchers aim to evaluate the effectiveness of inlexisertib alone and in combination with other drugs like trametinib, binimetinib (Mektovi), or sotorasib (Lumakras). The trial consists of two parts: determining the optimal dose and then assessing its effectiveness. Suitable candidates have a solid tumor with a RAS, NF1, or RAF mutation and have not responded to other treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

You may need to stop taking certain medications before joining the trial. Specifically, you must not have taken strong or moderate inhibitors or inducers of CYP3A4 or P-glycoprotein, including some herbal medications, within 14 days or 5 times the medication's half-life. Additionally, you must stop taking grapefruit products 14 days before starting the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that DCC-3116, when used alone, is generally safe for patients with certain advanced tumors. Early results indicate it has not caused major side effects in these patients.

When combined with trametinib, DCC-3116 has shown promising results in early lab studies. However, researchers are still carefully monitoring its safety in human trials. Similarly, early research suggests that combining it with sotorasib is also well-tolerated, but more information is needed to confirm this.

In studies where DCC-3116 was tested with binimetinib, it was found to be generally safe, though the long-term effects remain unknown.

Since this study is in its early stages, the main goal is to ensure these treatments are safe for humans. So far, no major safety issues have been reported, but researchers continue to gather data to confirm this. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about DCC-3116 and its combinations because these treatments target specific mutations in solid tumors, like KRAS G12C, which are often tough to treat. Unlike many standard treatments that broadly attack cancer cells, DCC-3116 works by potentially inhibiting specific pathways involved in cancer growth, offering a more targeted approach. This precision could lead to fewer side effects and more effective outcomes compared to traditional chemotherapy. Additionally, when combined with drugs like sotorasib, which specifically targets KRAS G12C mutations, there's a promising synergy that could enhance effectiveness against these stubborn cancer types.

What evidence suggests that this trial's treatments could be effective for solid tumors?

Research has shown that DCC-3116, also called inlexisertib, blocks certain proteins that help cancer cells survive. Early studies found that DCC-3116 is generally safe for patients with some advanced or spreading tumors. This trial will test DCC-3116 both as a monotherapy and in combination with other drugs like binimetinib, trametinib, or sotorasib. For instance, in studies with sotorasib, nearly one-third of patients with a specific type of lung cancer responded positively. Overall, DCC-3116 appears promising, especially when combined with other treatments targeting a common cancer pathway known as RAS/MAPK. ^{1 3 5 6 7}

Who Is on the Research Team?

Clinical Team

Principal Investigator

Deciphera Pharmaceuticals, LLC

Are You a Good Fit for This Trial?

Adults with advanced solid tumors having specific mutations (RAS/MAPK pathway) who've had certain prior treatments can join. They need good organ function, an ECOG score of 0-2, and must not be pregnant or breastfeeding. Contraception is required for both men and women.

Inclusion Criteria

My cancer has a KRAS G12C mutation.

I can provide a new or old sample of my tumor for the study.

I agree to follow the required contraception methods.

Exclusion Criteria

Known human immunodeficiency virus unless the following requirements are met:

I haven't taken any experimental drugs with unknown safety for at least 28 days, or 14 days with approval.

I stopped taking trametinib or binimetinib due to side effects.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

DCC-3116 is administered in escalating doses as monotherapy and in combination with other drugs to determine the maximum tolerated dose

Approximately 18 months

Expansion

DCC-3116 is administered in combination with sotorasib in 28-day cycles to evaluate safety and preliminary efficacy

Approximately 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Binimetinib
• DCC-3116
• Sotorasib
• Trametinib

Trial Overview The trial tests DCC-3116 alone or with trametinib, binimetinib, or sotorasib in two phases: dose escalation to find safe amounts and expansion to see effects on different cancers like colorectal cancer and melanoma.

How Is the Trial Designed?

Group I: Expansion Cohorts 1, 2, 3 and 4 (Part 2) Experimental Treatment 1 Intervention

Expansion Cohorts 1, 2, 3 and 4 inlexisertib combinations will not open for enrollment.

Group II: Expansion Cohort 5 (Part 2) Experimental Treatment 2 Interventions

Inlexisertib tablets orally given in combination with sotorasib in 28-day cycles to evaluate safety and preliminary efficacy of participants with NSCLC (with a documented mutation in KRAS G12C).

Group III: Dose Escalation (Part 1, Cohort D Combination) Experimental Treatment 2 Interventions

Upon determination of the RP2D/MTD single agent, inlexisertib will be dosed in combination with sotorasib.

Group IV: Dose Escalation (Part 1, Cohort C Combination) Experimental Treatment 2 Interventions

Upon determination of the RP2D/MTD single agent, inlexisertib will be dosed in combination with binimetinib. Escalation Cohort C combination closed on January 8, 2024.

Group V: Dose Escalation (Part 1, Cohort B Combination) Experimental Treatment 2 Interventions

Upon determination of the RP2D/MTD single agent, inlexisertib will be dosed in combination with trametinib. Escalation Cohort B combination closed on January 8, 2024.

Group VI: Dose Escalation (Part 1, Cohort A Monotherapy) Experimental Treatment 1 Intervention

Inlexisertib tablets in escalating dose cohorts given orally twice daily (BID) in 28-day cycles as monotherapy (single agent). If no DLT in 3 participants or 1 DLT/6 participants is observed, dose escalation may continue to the next planned dose cohort.

Binimetinib is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600E or V600K mutation

Approved in European Union as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation

Approved in Canada as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600E or V600K mutation

Approved in Japan as Mektovi for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation

Who Is Running the Clinical Trial?

Deciphera Pharmaceuticals LLC

Lead Sponsor

Trials

17

Recruited

1,900+

Deciphera Pharmaceuticals, LLC

Lead Sponsor

Trials

19

Recruited

2,100+

Published Research Related to This Trial

Temsirolimus, an mTOR-inhibitor, showed prolonged activity in a patient with desmoplastic small round cell tumor (DSRCT), suggesting potential therapeutic benefits for this aggressive cancer.

In vitro studies indicated that rapamycin can induce cell death in JN-DSRCT-1 cells, which may help in understanding the mechanism of action for mTOR inhibitors in treating DSRCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temsirolimus for metastatic desmoplastic small round cell tumor. Thijs, AM., van der Graaf, WT., van Herpen, CM.[2022]

The combination of encorafenib (ENC) and binimetinib (BIN) was found to be cost-effective compared to cobimetinib (COB) and vemurafenib (VEM) only at a very high willingness-to-pay threshold of $573,000 per quality-adjusted life year (QALY).

The combination of dabrafenib (DAB) and trametinib (TRA) was determined to be the most optimal treatment option for BRAF-mutated advanced melanoma, dominating the COB + VEM combination in terms of cost-effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Economic Evaluation of Three BRAF + MEK Inhibitors for the Treatment of Advanced Unresectable Melanoma With BRAF Mutation From a US Payer Perspective. Halloush, S., Alkhatib, NS., Almutairi, AR., et al.[2023]

The combination of sunitinib and tremelimumab in patients with metastatic renal cell carcinoma showed significant safety concerns, particularly with rapid-onset acute renal failure being the most common dose-limiting toxicity observed.

Despite the safety issues, the treatment demonstrated some efficacy, with 43% of evaluable patients achieving partial responses, indicating potential antitumor activity that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma. Rini, BI., Stein, M., Shannon, P., et al.[2020]

Sunitinib is an effective small-molecule inhibitor that targets receptor tyrosine kinases involved in tumor blood vessel formation, particularly the VEGF receptor, showing significant antiangiogenic effects in laboratory and animal studies.

In human trials, a daily dose of 50 mg has been found to be tolerable and effective, especially for advanced renal cell carcinoma and gastrointestinal stromal tumors that are resistant to imatinib, leading to its regulatory approval for these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sunitinib. Rini, BI.[2019]

Binimetinib, an uncompetitive inhibitor of MEK1/2, has shown significant efficacy in treating metastatic melanoma, particularly in combination with encorafenib, resulting in a progression-free survival (PFS) of 14.9 months compared to 7.3 months with vemurafenib alone in Phase 3 trials.

While binimetinib has a tolerable safety profile, there is currently no long-term data on durable responses or overall survival benefits compared to other treatments, highlighting the need for individualized treatment plans for patients with BRAF-mutated metastatic melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The discovery and development of binimetinib for the treatment of melanoma. Tran, B., Cohen, MS.[2021]

In a study of 35 patients with metastatic cutaneous melanoma and uveal melanoma treated with the MEK inhibitor binimetinib, 20% of cutaneous melanoma patients and 40% of uveal melanoma patients reported mild and transient visual symptoms, typically occurring within 3.5 days of starting treatment.

The study found that 77% of cutaneous melanoma patients and 60% of uveal melanoma patients developed subretinal fluid, indicating a reversible serous retinopathy associated with binimetinib, potentially linked to medication toxicity and the presence of autoantibodies against retinal proteins.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serous Retinopathy Associated with Mitogen-Activated Protein Kinase Kinase Inhibition (Binimetinib) for Metastatic Cutaneous and Uveal Melanoma. van Dijk, EH., van Herpen, CM., Marinkovic, M., et al.[2023]

In a study involving 28 patients with advanced biliary tract cancer, binimetinib was found to be well tolerated, with common mild side effects like rash (82%) and nausea (54%), and only two patients experienced severe adverse events.

Binimetinib demonstrated promising clinical activity, with 43% of patients achieving stable disease and two patients showing objective responses, including one complete response, suggesting its potential effectiveness in treating this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b investigation of the MEK inhibitor binimetinib in patients with advanced or metastatic biliary tract cancer. Finn, RS., Ahn, DH., Javle, MM., et al.[2019]

In a clinical trial involving 57 pretreated NSCLC patients, the combination of dabrafenib and trametinib showed a high overall response rate (ORR) of 68.4% and a median overall survival (OS) of 18.2 months, indicating its efficacy in treating BRAF V600E mutant non-small cell lung cancer.

The treatment was well tolerated, with manageable side effects such as pyrexia and nausea, leading to its approval for BRAF V600E metastatic NSCLC patients, regardless of prior therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BRAF Inhibitors in Non-Small Cell Lung Cancer. Sforza, V., Palumbo, G., Cascetta, P., et al.[2022]

In a phase 3 study involving 357 patients with advanced squamous non-small cell lung cancer (sqNSCLC), sintilimab combined with platinum and gemcitabine (GP) significantly improved progression-free survival (PFS) compared to GP alone, with a hazard ratio of 0.536, indicating a strong clinical benefit.

The safety profile of sintilimab-GP was acceptable, with similar rates of severe treatment-related adverse events (86.6% for sintilimab-GP vs. 83.1% for placebo-GP) and no new safety concerns identified, suggesting it is a viable first-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sintilimab Plus Platinum and Gemcitabine as First-Line Treatment for Advanced or Metastatic Squamous NSCLC: Results From a Randomized, Double-Blind, Phase 3 Trial (ORIENT-12). Zhou, C., Wu, L., Fan, Y., et al.[2022]

In a phase II study involving 98 patients with BRAFV600E-mutant metastatic non-small-cell lung cancer (NSCLC), the combination of encorafenib and binimetinib achieved a confirmed objective response rate of 75% in treatment-naïve patients and 46% in previously treated patients, indicating significant efficacy.

The treatment was generally well-tolerated, with common side effects including nausea (50%) and diarrhea (43%), but it also led to dose reductions in 24% of patients and one serious adverse event of intracranial hemorrhage, highlighting the importance of monitoring safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients With BRAFV600-Mutant Metastatic Non-Small-Cell Lung Cancer. Riely, GJ., Smit, EF., Ahn, MJ., et al.[2023]

In a Phase II trial involving 13 patients with desmoplastic small round cell tumor (DSRCT) who were unresponsive to conventional treatments, imatinib was administered at a dose of 400 mg daily.

The results showed that imatinib had no significant efficacy, with only one patient achieving stable disease and seven experiencing progressive disease after three months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imatinib mesylate in desmoplastic small round cell tumors. De Sanctis, R., Bertuzzi, A., Bisogno, G., et al.[2018]

In a phase II study involving 183 metastatic melanoma patients, binimetinib effectively inhibited the MAPK pathway, as evidenced by decreased levels of pERK and DUSP6 in tumor samples after treatment.

Despite the observed pathway inhibition, there was no direct correlation between reduced pERK or DUSP6 levels and clinical efficacy, suggesting that additional genetic factors, such as alterations in CDKN2A/B and PTEN, may influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomarker results from a phase II study of MEK1/2 inhibitor binimetinib (MEK162) in patients with advanced NRAS- or BRAF-mutated melanoma. van Herpen, CML., Agarwala, SS., Hauschild, A., et al.[2020]

In a study involving 21 Japanese patients with advanced solid tumors, binimetinib was found to have an acceptable safety profile, with the maximum tolerated dose established at 45 mg taken twice daily, despite some patients experiencing reversible retinal adverse events.

While no complete or partial responses were observed, 67% of patients achieved stable disease for over 180 days, indicating that binimetinib can effectively stabilize tumor growth in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of binimetinib (MEK162) in Japanese patients with advanced solid tumors. Watanabe, K., Otsu, S., Hirashima, Y., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04892017

A Phase 1/2 Study of Inlexisertib (DCC-3116) in Patients ... This is a Phase 1/2, multicenter, open label, first in human (FIH) study of inlexisertib as monotherapy, and in combination with trametinib, binimetinib, ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.TPS3178

A phase 1/2 study of DCC-3116 as a single agent and in ... DCC-3116 is a potent and selective ULK inhibitor that showed preclinical antitumor activity in combination with the MAPK kinase inhibitor trametinib.

3. deciphera.com deciphera.com/sites/default/files/publication-files/DCPH%20DCC-3116%20Overview%20and%20Preclinical%20Data_April%2015%2C%202022.pdf

DCC-3116 Overview and Preclinical Data Histologically confirmed diagnosis of an advanced or metastatic solid tumor with a documented RAS or RAF mutation. DCC-3116 | PHASE 1 STUDY.

4. onclive.com onclive.com/view/dcc-3116-displays-early-tolerability-in-ras-raf-mutant-solid-tumors

DCC-3116 Displays Early Tolerability in RAS/RAF-Mutant ... The ULK1/2 inhibitor DCC-3116 was well tolerated as a monotherapy in patients with locally advanced or metastatic tumors harboring a RAS or RAF mutation.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05957367

NCT05957367 | A Study of Inlexisertib (DCC-3116) in ... Inlexisertib tablets will be administered in combination with ripretinib in 28-day cycles to evaluate preliminary efficacy in participants with 2nd-line ...

6. deciphera.com deciphera.com/pipeline/dcc-3116

DCC-3116 DCC-3116 is being investigated in a Phase 1/2 study designed to evaluate the safety, tolerability, clinical activity, pharmacokinetics, and pharmacodynamics of ...

7. uclahealth.org uclahealth.org/clinical-trials/study-inlexisertib-dcc-3116-combination-with-anticancer

A Study of Inlexisertib (DCC-3116) in Combination With ... ... Solid Tumors (mRECIST); Must have a life expectancy of more than 3 months and an ECOG performance status of 0-1; Adequate organ function and bone marrow ...